Yes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma
Open accessAbstract
Background & aims Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear.Methods By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients.Results Human HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer.Conclusions The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).
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A number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU, and small molecules such as verteporfin and MGH-CP1.
“Over the years, a number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU (173),437 and small molecules such as verteporfin (174) and MGH-CP1 (175).438–440”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [439]
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Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
Kim, W., Khan, S. K., Gvozdenovic-Jeremic, J., Kim, Y., Dahlman, J., Kim, H., Park, O., Ishitani, T., Jho, E.-H., Gao, B., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci88486 · Cited by 244 · see citing works
YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
Fitamant, J., Kottakis, F., Benhamouche, S., Tian, H. S., Chuvin, N., Parachoniak, C. A., Nagle, J. M., Perera, R. M., Lapouge, M., Deshpande, V., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.027 · Cited by 248 · see citing works
YAP activation is an early event and a potential therapeutic target in liver cancer development
Perra, A., Kowalik, M. A., Ghiso, E., Ledda‐Columbano, G. M., Tommaso, L. D., Angioni, M. M., Raschioni, C., Testore, E., Roncalli, M. G., Giordano, S., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.06.033 · Cited by 240 · see citing works
Hippo Signaling in Embryogenesis and Development
Wu, Z., & Guan, K. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.08.008 · Cited by 237 · see citing works
“2): NICD is reported to enhance YAP/TAZ activity by promoting protein stability and YAP/TAZ can activate the transcription of Notch receptors and its ligand, JAG1 (Jagged Canonical Notch Ligand 1) [48, 49].”
BackgroundMarti, P., Stein, C., Blumer, T., Abraham, Y., Dill, M. T., Pikiolek, M., Orsini, V., Jurisic, G., Megel, P., Makowska, Z., et al. (2015) · Hepatology · doi:10.1002/hep.27992 · Cited by 232 · see citing works
“Increasing evidence implicates deregulation of the YAP/Hippo pathway in a variety of cancers.(12,14,18-24) Given the important role of YAP in promoting proliferation, differentiation, and antiapoptotic mechanisms in organ development and regeneration, it is not surprising that deregulation of YAP eventually results in…”
BackgroundNotch and Hippo Converge on Cdx2 to Specify the Trophectoderm Lineage in the Mouse Blastocyst
Rayón, T., Menchero, S., Nieto, A., Xenopoulos, P., Crespo, M., Cockburn, K., Cañón, S., Sasaki, H., Hadjantonakis, A., de la Pompa, J. L., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.06.019 · Cited by 231 · see citing works
A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy
Pobbati, A. V., & Hong, W. (2020) · Theranostics · doi:10.7150/thno.40889 · Cited by 223 · see citing works
Deng, F., Peng, L., Li, Z., Tan, G., Liang, E., Chen, S., Zhao, X., & Zhi, F. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0244-8 · Cited by 208 · see citing works
Pobbati, A. V., Han, X. Y., Hung, A. W., Seetoh, W.-G., Huda, N., Chen, G.-Y., Kang, C., Chia, C. S. B., Luo, X., Hong, W., et al. (2015) · Structure · doi:10.1016/j.str.2015.09.009 · Cited by 212 · see citing works
Hippo signalling in the liver: role in development, regeneration and disease
Russell, J. O., & Camargo, F. D. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00571-w · Cited by 205 · see citing works
Song, S., Xie, M., Scott, A. W., Jin, J., Ma, L., Dong, X., Skinner, H. D., Johnson, R. L., Ding, S., & Ajani, J. A. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0560 · Cited by 200 · see citing works
Exploration of liver cancer genomes
Shibata, T., & Aburatani, H. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2014.6 · Cited by 197 · see citing works
Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice
Nishio, M., Sugimachi, K., Goto, H., Wang, J. H., Morikawa, T., Miyachi, Y., Takano, Y., Hikasa, H., Itoh, T., Suzuki, S. O., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1517188113 · Cited by 190 · see citing works
“preventing it from activating TEA domain family member (TEAD)-mediated transcription of connective tissue growth factor (CTGF) (9), secreted phosphoprotein 1 (SPP1) (10), transforming growth factor beta (TGFβ) (11), and Jagged 1 (JAG1) (12).”
BackgroundInfluentialLiver Regeneration: Analysis of the Main Relevant Signaling Molecules
Tao, Y.-C., Wang, M.-L., Chen, E., & Tang, H. (2017) · Mediators of Inflammation · doi:10.1155/2017/4256352 · Cited by 191 · see citing works
“YAP-mediated induction of Jag-1 was able to activate Notch signaling in HCC and mouse hepatocytes [19].”
BackgroundThe Notch ligand Jagged1 as a target for anti-tumor therapy
Li, D. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00254 · Cited by 188 · see citing works
A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy
Shibata, M., Ham, K., & Hoque, M. O. (2018) · International Journal of Cancer · doi:10.1002/ijc.31561 · Cited by 188 · see citing works
Lee, D.-H., Park, J. O., Kim, T.-S., Kim, S.-K., Kim, T.-H., Kim, M.-C., Park, G. S., Kim, J.-H., Kuninaka, S., Olson, E. N., et al. (2016) · Nature Communications · doi:10.1038/ncomms11961 · Cited by 196 · see citing works
gp130 Controls Cardiomyocyte Proliferation and Heart Regeneration
Li, Y., Feng, J., Song, S., Li, H., Yang, H., Zhou, B., Li, Y., Zhang, Y., Lian, H., Liu, L., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044484 · Cited by 177 · see citing works
Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer
Yimlamai, D., Fowl, B. H., & Camargo, F. D. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.07.008 · Cited by 174 · see citing works
The Hippo pathway in normal development and cancer
Maugeri‐Saccà, M., & Maria, R. D. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.12.011 · Cited by 165 · see citing works
Holden, J. K., Crawford, J. J., Noland, C. L., Schmidt, S., Zbieg, J. R., Lacap, J. A., Zang, R., Miller, G. M., Zhang, Y., Beroza, P., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107809 · Cited by 166 · see citing works
Jin, M., Wang, J., Ji, X., Cao, H., Zhu, J., Chen, Y., Jin, Y., Zhao, Z., Ren, T., & Xing, J. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1135-x · Cited by 162 · see citing works
Pediatric hepatocellular carcinoma
Khanna, R., & Verma, S. K. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i35.3980 · Cited by 160 · see citing works
Crosstalk between YAP/TAZ and Notch Signaling
Totaro, A., Castellan, M., Biagio, D. D., & Piccolo, S. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.03.001 · Cited by 163 · see citing works
“Interestingly Jag1 is a YAP target in hepatocytes [44] and human hepatocellular carcinoma [51].”
BackgroundControl of Proliferation and Cancer Growth by the Hippo Signaling Pathway
Ehmer, U., & Sage, J. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0305 · Cited by 156 · see citing works
“There is strong evidence that the Notch pathway is activated by YAP through direct transcriptional targeting of JAG1 in the liver (27, 50).”
BackgroundWeiler, S. M. E., Pinna, F., Wolf, T., Lutz, T., Geldiyev, A., Sticht, C., Knaub, M., Thomann, S., Bissinger, M., Wan, S., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.02.018 · Cited by 155 · see citing works
Self-citationZhou, Z., Hu, T., Xu, Z., Lin, Z., Zhang, Z., Feng, T., Zhu, L., Rong, Y., Shen, H. C., Luk, J. M., et al. (2014) · The FASEB Journal · doi:10.1096/fj.14-262980 · Cited by 144 · see citing works
Xiao, S., Chang, R., Yang, M., Lei, X., Liu, X., Gao, W., Xiao, J., & Yang, L. (2015) · Hepatology · doi:10.1002/hep.28417 · Cited by 143 · see citing works
“Notch signaling is critical for tissue and organ development; recent advances have also confirmed that Notch played a very important role in progression of HCC.(18,35) However, which member of Notch1-4 plays the predominant role in HCC is still controversial.”
BackgroundResultInfluentialYamada, D., Ilyas, S. I., Razumilava, N., Bronk, S. F., Davila, J. I., Champion, M. D., Borad, M. J., Bezerra, J. A., Chen, X., & Gores, G. J. (2015) · Hepatology · doi:10.1002/hep.27687 · Cited by 142 · see citing works
“Additionally, it has recently been demonstrated that YAP activates the Notch pathway by up-regulating jagged 1 in human hepatocellular carcinoma.(27) To further elucidate whether these tumors recapitulate these human phenotypes, Notch and IL-6 pathways were investigated.”
BackgroundSelf-citationIL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19
Kishimoto, T., & Kang, S. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-023458 · Cited by 140 · see citing works
Rozengurt, E., Sinnett‐Smith, J. W., & Eibl, G. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-017-0005-2 · Cited by 135 · see citing works
Hippo Pathway Regulation of Gastrointestinal Tissues
Yu, F., Meng, Z., Plouffe, S. W., & Guan, K. (2014) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021014-071733 · Cited by 138 · see citing works
“In the mouse intestine, Yap overexpression or Mst1/2 deletion results in Notch activation (96, 97), and the Notch ligand Jagged-1 is induced by Yap (98).”
Hayashi, H., Higashi, T., Yokoyama, N., Kaida, T., Sakamoto, K., Fukushima, Y., Ishimoto, T., Kuroki, H., Nitta, H., Hashimoto, D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0291 · Cited by 135 · see citing works
“Several studies have demonstrated the overexpression of TAZ or YAP in human cancers, including HCC (9-17).”
BackgroundMolecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Self-citationYAP regulates PD-L1 expression in human NSCLC cells
Miao, J., Hsu, P., Yang, Y., Xu, Z., Dai, Y., Wang, Y., Chan, G., Huang, Z., Hu, B., Li, H., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.23051 · Cited by 130 · see citing works
Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis
Liu, Y., Zhuo, S., Zhou, Y., Ma, L., Sun, Z., Wu, X., Wang, X. W., Gao, B., & Yang, Y. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.11.010 · Cited by 129 · see citing works
Epithelial Plasticity during Liver Injury and Regeneration
Gadd, V. L., Aleksieva, N., & Forbes, S. J. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.08.016 · Cited by 142 · see citing works
Liu, C., Liu, L., Chen, X., Cheng, J., Zhang, H., Zhang, C., Shan, J., Shen, J., & Qian, C. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1236 · Cited by 129 · see citing works
Self-citationMoore, G., Annett, S., McClements, L., & Robson, T. (2020) · Cells · doi:10.3390/cells9061503 · Cited by 129 · see citing works
Chen, Y., Ling, Z., Cai, X., Xu, Y., Lv, Z., Man, D., Ge, J., Yu, C., Zhang, D., Zhang, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1628 · Cited by 121 · see citing works
Abitbol, S., Dahmani, R., Coulouarn, C., Ragazzon, B., Mlecnik, B., Senni, N., Savall, M., Bossard, P., Sohier, P., Drouet, V., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.12.018 · Cited by 118 · see citing works
Williamson, K. A., Rainger, J., Floyd, J. A. B., Ansari, M., Meynert, A. M., Aldridge, K. V., Rainger, J. K., Anderson, C. A., Moore, A. T., Hurles, M. E., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.01.001 · Cited by 112 · see citing works
The Carcinogenic Role of the Notch Signaling Pathway in the Development of Hepatocellular Carcinoma
Huang, Q., Li, J., Zheng, J., & Wei, A. (2019) · Journal of Cancer · doi:10.7150/jca.26847 · Cited by 111 · see citing works
Hepatic Notch Signaling Correlates With Insulin Resistance and Nonalcoholic Fatty Liver Disease
Valenti, L. V. C., Mendoza, R. M., Rametta, R., Maggioni, M., Kitajewski, C., Shawber, C. J., & Pajvani, U. B. (2013) · Diabetes · doi:10.2337/db13-0769 · Cited by 109 · see citing works
The mammalian Hippo pathway: regulation and function of YAP1 and TAZ
Kodaka, M., & Hata, Y. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1742-9 · Cited by 108 · see citing works
“In hepatocellular carcinomas, YAP1 up-regulates Jagged-1 and stimulates Notch signaling in a non-cell autonomous manner [163].”
Yi, J., Lu, L., Yanger, K., Wang, W., Sohn, B. H., Stanger, B. Z., Zhang, M., Martin, J. F., Ajani, J. A., Chen, J., et al. (2016) · Hepatology · doi:10.1002/hep.28768 · Cited by 105 · see citing works
“YAP directly regulates the expression of key factors that promote biliary epithelial development, including Sox9((36)) and components of the notch signaling pathway.((27,28)) Indeed, when YAP is activated by LATS1/2 depletion, we observed an increase in the number of HNF4a/Sox9 double- positive cells and an increase i…”
BackgroundYu, W., Qiao, Y., Tang, X., Ma, L., Wang, Y., Zhang, X., Weng, W., Pan, Q., Yu, Y., Sun, F., et al. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.09.011 · Cited by 102 · see citing works
Differential effects of targeting Notch receptors in a mouse model of liver cancer
Huntzicker, E. G., Hötzel, K., Choy, L., Che, L., Ross, J., Pau, G., Sharma, N., Siebel, C. W., Chen, X., & French, D. M. (2014) · Hepatology · doi:10.1002/hep.27566 · Cited by 100 · see citing works
“Although multiple studies have attempted to determine the expression pattern of Notch1 in human HCC samples, the results have thus far been inconsistent and controversial, from membrane or cytoplasm staining in 50% of HCC samples(20) with no nuclear localization of Notch1 in HCCs to nuclear staining of Notch1 in 49% o…”
BackgroundSelf-citationHippo signaling is required for Notch-dependent smooth muscle differentiation of neural crest
Manderfield, L. J., Aghajanian, H. K., Engleka, K. A., Lim, L. Y., Lui, F., Jain, R., Li, L., Olson, E. N., & Epstein, J. A. (2015) · Development · doi:10.1242/dev.125807 · Cited by 100 · see citing works
Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies
Lee, Y. A., & Friedman, S. L. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13380 · Cited by 102 · see citing works
Hippo‐YAP signaling pathway: A new paradigm for cancer therapy
Ma, Y., Yang, Y., Wang, F., Wei, Q., & Qin, H. (2014) · International Journal of Cancer · doi:10.1002/ijc.29073 · Cited by 99 · see citing works
“A higher expression of YAP correlated with Jag-1 expression and Notch signaling in tumor samples and with shorter survival times of patients with HCC or colorectal cancer, indicating the utility of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer.(62) The roles of miRNA and lncRNA in tumorigenesis…”
BackgroundNovel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation
Grampa, V., Delous, M., Zaidan, M., Odye, G., Thomas, S., Elkhartoufi, N., Filhol-Blin, E., Niel, O., Silbermann, F., Lebreton, C., et al. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1005894 · Cited by 94 · see citing works
Proliferative polyploid cells give rise to tumors via ploidy reduction
Matsumoto, T., Wakefield, L., Peters, A., Peto, M., Spellman, P., & Grompe, M. (2021) · Nature Communications · doi:10.1038/s41467-021-20916-y · Cited by 77 · see citing works
The oncogenic role of Jagged1/Notch signaling in cancer
Xiu, M., Liu, Y., & Kuang, B. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110416 · Cited by 93 · see citing works
YAP and TAZ Take Center Stage in Cancer
Zhang, K., Qi, H.-X., Hu, Z., Chang, Y., Shi, Z., Han, X., Han, Y., Zhang, R., Zhang, Z., Chen, T., et al. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b01014 · Cited by 93 · see citing works
de Lima, J. E., Bonnin, M.-A., Birchmeier, C., & Duprez, D. (2016) · eLife · doi:10.7554/elife.15593 · Cited by 89 · see citing works
“Oncogenic YAP variants activate the NOTCH ligand JAG1 and consequently NOTCH signaling in hepatocellular carcinoma cells (Tschaharganeh et al., 2013).”
BackgroundThe Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors
Hagenbeek, T. J., Webster, J. D., Kljavin, N. M., Chang, M. T., Pham, T., Lee, H.-J., Klijn, C. N., Cai, A. G., Tótpál, K., Ravishankar, B., et al. (2018) · Science Signaling · doi:10.1126/scisignal.aaj1757 · Cited by 89 · see citing works
A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma
Aihara, A., Huang, C.-K., Olsen, M. J., Lin, Q., Chung, W., Tang, Q., Dong, X., & Wands, J. R. (2014) · Hepatology · doi:10.1002/hep.27275 · Cited by 88 · see citing works
Emerging role of Hippo pathway in gastric and other gastrointestinal cancers
Kang, W. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i3.1279 · Cited by 85 · see citing works
The Hippo signaling pathway provides novel anti-cancer drug targets
Bae, J. S., Kim, S. M., & Lee, H. (2016) · Oncotarget · doi:10.18632/oncotarget.14306 · Cited by 86 · see citing works
“A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency.”
BackgroundLiver Inflammation and Hepatobiliary Cancers.
Leone, V., Ali, A., Weber, A., Tschaharganeh, D., & Heikenwalder, M. (2021) · Trends in Cancer · doi:10.1016/j.trecan.2021.01.012 · Cited by 79 · see citing works
Self-citationZhang, X., Liu, X., Luo, J., Xiao, W. L., Ye, X., Chen, M., Li, Y., & Zhang, G.-J. (2016) · Oncogenesis · doi:10.1038/oncsis.2016.67 · Cited by 81 · see citing works
Shome, D., von Woedtke, T., Riedel, K., & Masur, K. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/4910280 · Cited by 80 · see citing works
Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor
Sebio, A., & Lenz, H. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0411 · Cited by 80 · see citing works
“The expression of the Notch ligand Jagged-1 is upregulated by nuclear YAP in colorectal and hepatocarcinoma tissue samples and correlates with the patient survival (28).”
BackgroundWatanabe, Y., Miyasaka, K. Y., Kubo, A., Kida, Y. S., Nakagawa, O., Hirate, Y., Sasaki, H., & Ogura, T. (2017) · Scientific Reports · doi:10.1038/srep46135 · Cited by 80 · see citing works
Regulation of the Hippo pathway in cancer biology
Moon, S., Park, S. Y., & Park, H. W. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2804-1 · Cited by 76 · see citing works
Hippo Signaling in the Liver – A Long and Ever-Expanding Story
Manmadhan, S., & Ehmer, U. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00033 · Cited by 77 · see citing works
“In contrast, Wnt signaling has been shown to inhibit hepatic YAP/TAZ signaling – in part by interfering with the NotchYAP feedback loop (Tschaharganeh et al., 2013; Kim et al., 2017b,c).”
The history and regulatory mechanism of the Hippo pathway
Kim, W., & Jho, E. (2018) · BMB Reports · doi:10.5483/bmbrep.2018.51.3.022 · Cited by 77 · see citing works
“positive feedback loop during tumorigenesis (120, 134, 138).”
BackgroundYAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo
Sun, D., Li, X.-T., He, Y., Li, W., Wang, Y., Wang, H., Jiang, S., & Xin, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.13188 · Cited by 76 · see citing works
“Furthermore, YAP1 (located on 11q22) has been identified as a candidate oncogene in several cancers; its overexpression and increased nuclear localization have been reported in breast cancer [8], hepatocellular carcinoma [10], colorectal cancer [11], GC [12], pancreatic cancer [13], and esophageal squamous cell carcin…”
BackgroundWei, T., Weiler, S. M. E., Tóth, M., Sticht, C., Lutz, T., Thomann, S., Torre, C. D. L., Straub, B. K., Merker, S., Ruppert, T., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0801-y · Cited by 76 · see citing works
Self-citationFerguson, G. B., & Martínez-Agosto, J. A. (2014) · Current Biology · doi:10.1016/j.cub.2014.09.081 · Cited by 76 · see citing works
Li, M., Lu, J., Zhang, F., Li, H., Zhang, B., Wu, X., Tan, Z., Zhang, L., Gao, G., Mu, J., et al. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.08.036 · Cited by 74 · see citing works
Recent Advances of the Hippo/YAP Signaling Pathway in Brain Development and Glioma
Ouyang, T., Meng, W., Li, M., Hong, T., & Zhang, N. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00762-9 · Cited by 73 · see citing works
Ren, K., Li, T., Zhang, W., Ren, J., Li, Z., & Wu, G. (2016) · Journal of Biomedical Science · doi:10.1186/s12929-016-0295-7 · Cited by 72 · see citing works
The Ambivalent Function of YAP in Apoptosis and Cancer
Zhang, X., Abdelrahman, A., Vollmar, B., & Zechner, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123770 · Cited by 71 · see citing works
“Decreased Increased 27307755 [32] Lung shRNA 25665005 [33] Breast shRNA 28892790 [18] Stomach siRNA 27073556 [34] Stomach siRNA 21805037 [35] Liver siRNA 23419361 [36] Liver siRNA 27323827 [37] Liver siRNA 29928445 [38] Pancreas siRNA 27738325 [39] Pancreas siRNA 27669292 [40] Pancreas siRNA 22396793 [41] Colon/Rectum…”
BackgroundHepatic Hippo signaling inhibits development of hepatocellular carcinoma
Liu, Y.-C., Wang, X.-H. L., & Yang, Y.-Z. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0178 · Cited by 65 · see citing works
“In human HCC, a Notch ligand JAGGED 1 (JAG 1) has been identified as a direct YAP downstream target contributes to high Notch signaling activity in tumor.(65) In mice, Notch ligand JAG 1 and Notch receptor Notch2 have been also identified as downstream targets of YAP.”
BackgroundLiu, M., Yan, Q., Sun, Y. J., Nam, Y., Hu, L., Loong, J. H. C., Ouyang, Q., Zhang, Y., Li, H., Kong, F.-E., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1912146117 · Cited by 63 · see citing works
Self-citationLi, X., Tao, J., Cigliano, A., Sini, M., Caldéraro, J., Azoulay, D., Wang, C., Liu, Y., Jiang, L., Evert, K., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3546 · Cited by 65 · see citing works
Self-citationTGF-β1 and TGF-β2 abundance in liver diseases of mice and men
Dropmann, A., Dediulia, T., Breitkopf‐Heinlein, K., Korhonen, H., Janicot, M., Weber, S. N., Thomas, M., Piiper, A., Bertrán, E., Fabregat, I., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6967 · Cited by 64 · see citing works
“uncovered a universal organ size control mechanism in metazoan, showing that Yap overexpression in the liver increased liver mass in transgenic mice extensively and strongly induced TGF-β2 expression [51, 52].”
BackgroundA Novel Notch–YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma
Slemmons, K. K., Crose, L. E. S., Riedel, S., Sushnitha, M., Belyea, B., & Linardic, C. M. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0004 · Cited by 62 · see citing works
“For example, in neural stem cells Notch transcriptionally regulates YAP (27), while in intestinal stem cells (28, 29), adult hepatocytes (30), colon cancer cells (29), and hepatocellular carcinoma (31), YAP activates Notch.”
BackgroundThe roles of signaling pathways in liver repair and regeneration
Valizadeh, A., Majidinia, M., Kafil, H. S., Yousefi, M., & Yousefi, B. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28336 · Cited by 64 · see citing works
“Some genes (such as connective tissue growth factor, JAG1, and Notch‐2, which direct hippo signaling targets; Tschaharganeh et al., 2013) are cardinal for nuclear localization of YAP and TAZ for liver growth and regeneration (Zhao & Ye, 2008) In this regard, transgenic over- expression of YAP in…”
Roles of the H ippo pathway in lung development and tumorigenesis
Yeung, B., Yu, J., & Yang, X. (2015) · International Journal of Cancer · doi:10.1002/ijc.29457 · Cited by 63 · see citing works
“In addition, TAZ/YAP may activate different downstream targets in different cell types (57, 70-73).”
BackgroundWang, J., Tang, X., Weng, W., Qiao, Y., Lin, J., Liu, W., Liu, R., Ma, L., Yu, W., Yu, Y., et al. (2015) · Oncogene · doi:10.1038/onc.2015.36 · Cited by 62 · see citing works
- Authors
- Tschaharganeh, D. F., Chen, X., Latzko, P., Malz, M., Gaida, M. M., Felix, K., Ladu, S., Singer, S., Pinna, F., Gretz, N., Sticht, C., Tomasi, M. L., Delogu, S., Evert, M., Fan, B., Ribback, S., Jiang, L., Brozzetti, S., Bergmann, F., Dombrowski, F., Schirmacher, P., Calvisi, D. F., & Breuhahn, K.
- Affiliations
- University Hospital Heidelberg (DE)
- University of California, San Francisco (US)
- University of Chieti-Pescara (IT)
- Medizinische Fakultät Mannheim (DE)
- University of Southern California (US)
- Universität Greifswald (DE)
- Sapienza University of Rome (IT)
- Corresponding author
- Breuhahn, Kai
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 144
- Issue
- 7
- Pages
- 1530-1542.e12
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3665638
- OpenAlex
- W2060323466
- Cited by
- 326
- References
- 47
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 16 · 2023: 19 · 2022: 26 · 2021: 29 · 2020: 35 · 2019: 26 · 2018: 26 · 2017: 25 · 2016: 28 · 2015: 35 · 2014: 28 · 2013: 8 · 2012: 1
- FWCI
- 19.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- YAP, Jagged1, Notch signaling, hepatocellular carcinoma, TEAD4, MST1/2, Hippo signaling pathway, colorectal cancer, pancreatic cancer, cell proliferation, patient survival, transcriptional coactivator, therapeutic target
- MeSH terms
- Serrate-Jagged Proteins, Jagged-1 Protein, YAP-Signaling Proteins, TEA Domain Transcription Factors, Animals, Calcium-Binding Proteins, DNA-Binding Proteins, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Proteins, Muscle Proteins, Phosphoproteins, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Hepatocytes, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Receptors, Notch
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